From Natural Products to Chemical Probes: Discovery, Design, and Biological Insight

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ID: 339496
2026
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Abstract
Macrocyclic natural products possess conformationally defined structures that enable recognition of complex biomolecular surfaces, making them attractive scaffolds for modulating protein-protein interactions (PPIs). In this review, I highlight how chemical probes derived from marine natural products have uncovered new molecular mechanisms. Photoaffinity probes of the actin-targeting macrolides aplyronine A and mycalolide C revealed β-tubulin as the secondary target. Aplyronine A induces an actin-tubulin interaction that suppresses microtubule assembly, whereas mycalolide C directly binds tubulin and enhances paclitaxel-induced microtubule assembly. Chemical probe studies of the cyclic peptide stylissatin A identified lysosomal protective protein/cathepsin A as a target and revealed inhibition of its interaction with neuraminidase 1, linking lysosomal PPI modulation to lipid metabolism. I also describe ligand-dissociation-type N,N-dimethylaminopyrene probes that enable sensitive mass-spectrometric mapping of ligand-binding sites. These studies demonstrate how chemical probes can transform bioactive natural products into tools for target discovery, mechanistic analysis, and molecular design.
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Authors Masaki Kita
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Journal The Journal of Biochemistry
Year 2026
DOI
10.1093/jb/mvag076
URL
https://doi.org/10.1093/jb/mvag076
Keywords Keywords not found

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